Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission with an estimated annual incidence of about 1-2 per 100,000 and prevalence as high as 20-50 per 100,000. Treatment consists of symptomatic therapy with acetylcholinesterase inhibitors and immunotherapy such as corticosteroids, azathioprine, cyclosporine, and plasma exchange (PLEX) and intravenous immunoglobulin (IVIg). Despite current therapies, subset of patients remains medically refractory or has intolerable medication adverse effects. There is need for another agent in the management of MG as there are few effective drugs. Safe, well- tolerated, efficacious and steroid-sparing therapeutics are very desirable. Our proposed research will be instrumental in identifying a novel treatment strategy for MG that may be more effective than current approaches. Several recent studies, including two performed by our group, have demonstrated the benefits of B cell depletion rituximab treatment in MG patients. We completed a small retrospective study to evaluate B cell targeted therapy in medically refractory generalized MG. In this analysis we showed that rituximab led to a sustained clinical improvement in parallel to a reduction or discontinuation of other immunotherapies. We now plan on conducting a multicenter randomized, double-blind, placebo controlled Phase II clinical trial utilizing a futility design. The study would include acetylcholie receptor (AChR) antibody positive generalized MG patients. This study also presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that participate in the immunopathology of the disease. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying treatment of MG with rituximab leading to new ways to treat the disease. The specific primary aim of this study is to determine whether rituximab is safe and shows sufficient promise as a steroid sparing therapeutic for MG to warrant further study in a phase III efficacy trial. Additionally, we plan on collecting specimens to conduct an ancillary exploratory biomarker study, funded by NIAID, focused on identifying how treatment modifies the immunopathology of MG.